Project Summary/Abstract Benign prostatic hyperplasia (BPH) is the most common tumor-like condition in men over the age of 50. 50% of men between the ages of 51-60 will suffer from BPH-associated symptoms increasing to 90% in men older than 80 years. However, BPH remains poorly understood from a mechanistic basis. BPH treatment involves the use of ?1-adrenergic blockers (?-blockers), 5?-reductase inhibitors (5ARI) or the combination of the two. Although BPH patients are treated fairly uniformly, for a large subset of patients these types of treatments either fail to ease symptoms, or symptoms become worse resulting in surgical intervention. To date there is little understanding of what causes progression of BPH from asymptomatic to symptomatic to therapy resistant. Although various systemic stresses such as obesity and type 2 diabetes are seen in BPH patients, there is little understanding of how these comorbidities contribute to the progression of the condition. Our laboratory recently discovered that the loss of response to 5ARI therapy and progression to surgery in BPH patients may be associated with stress factors including activator protein-1 (AP-1) transcription factor expression, suggesting mechanisms similar to the responses seen in autoimmune inflammatory (AI) conditions such as rheumatoid arthritis and psoriasis. AP-1 factor family members play a role in the mediation of cellular response to oxidative stress and pro-inflammatory stimuli. Thus, we hypothesize that obesity and diabetes will give rise to distinct patterns of inflammation and associated AP-1 factor expression. As such we have proposed two aims to address our research question: (1) to determine inflammatory infiltration and associated AP-1 factor expression and (2) to determine the effects of autoimmunity on inflammatory infiltration, AP-1 factor signaling and prostate pathobiology. We will define the role of systemic stresses due to autoimmunity and diabetes in regulating AP-1 transcription factor responses in BPH and will also determine if the usage of drugs utilized in the treatment of AI disease will attenuate the progression of BPH. The data from this study will allow us to explore some of the factors believed to contribute to the progression of BPH and determine if drug regimens that affect such pathways alter the progression of the disease.